Ashleigh Hampton, MSc.
March 21, 2011
Note – the following is a summary adapted from the Ministry of Health’s Draft Guidance Document titled “Hepatotoxicity of Health Products”
Hepatotoxicity is characterized damage to the liver which may be associated with impaired liver function. Substance-induced hepatotoxicity is one of the most common causes of termination of health product development and the single most important cause of the withdrawal of market authorization for health products.
Hepatotoxicity may result from direct action of the health product or its metabolites, or indirectly from interactions with other health products, such as foods or xenobiotics. Furthermore, substance-induced hepatotoxicity may occur as an expected dose-dependent hepatic toxicity or as an unexpected idiosyncratic reaction. There are currently no standard criteria in place to diagnose health product-induced hepatotoxicity. The purpose of this Draft Guidance Document is to develop and provide basic guidance for the detection, assessment and mitigation of health-product induced hepatotoxicity.
Assessing Liver Function and Injury
Hepatic injury may result from direct damage to the hepatocytes or from damage which indirectly affects the hepatocytes. The liver is resilient and possesses the ability to regenerate itself as an adaptive response to many agents such that hepatic injury may not always lead to clinically decreased liver function.
Liver injury is associated with a wide range of pathology. Identification of clinical hepatotoxicity involves specific changes in the following pathological markers: alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), γ-glutamyltransferase (GGT), bilirubin, prothrombin time and bile acids. Elevation of these markers beyond normal upper limits is a sign of hepatic injury, and should be monitored.
Alanine Aminotransferase (ALT):
ALT is considered to be a more sensitive and specific indicator than AST for liver inflammation and hepatocyte necrosis. ALT rises very rapidly in plasma of patients with acute damage to the hepatocytes. If the hepatic injury is a result of by biliary obstruction, rather than inflammation or necrosis, then the increase in ALT tends to be slower and is usually accompanied by increase in ALP and GGT.
Aspartate Aminotransferase (AST):
AST is found in many tissues and may increase even if there is no hepatic injury. Typically, the increase in AST is usually less than the increase in ALT. However, levels of AST higher than ALT may suggest alcohol-induced injury.
Alkaline Phosphatase (ALP):
High ALP typically indicates either liver bile duct damage or duct blockage. This increase in ALP is usually accompanied by an increase in GGT or 5′-nucleotidase. However, it is important to note that ALP may also be increased due to causes unrelated to the liver.
GGT is a highly sensitive marker of hepatobiliary disease, but is not specific to hepatotoxicity only. Increases in GGT levels can be triggered by pathological conditions involving the heart, kidneys and pancreas as well as the liver. As a marker, CGT is typically used to exclude a skeletal source of elevated serum ALP.
Bilirubin is the most common marker used to screen for hepatic function. Elevated levels of bilirubin are used to differentiate cholestasis from hepatocellular injury. Cholestatic injury is the result of a stoppage or suppression of bile flow which leads to an increase in the levels of bile salts, whereas hepatocellular injury is typically the result of damage caused by infection or exposure to xenobiotics, such as alcohol or certain health products.
Prothombin is a protein produced by the liver and is also present in the plasma. Physiologically, prothrombin is converted to thrombin during blood clotting. Additionally, most other clotting factors are produced by the liver as well. Deficiency of one or more of the liver-produced factors results in a prolonged prothrombin time, i.e. an increase in the time it takes the plasma to coagulate, which can be used as a marker to assess the severity and prognosis of acute liver disease.
Bile acids are produced from cholesterol in the liver. Serum total bile acid has been used as an indicator for hepatic function for various types of chemical-induced hepatotoxicity. Furthermore, elevated level of serum bile acids act as an indication of hepatobiliary dysfunction, but cannot be used to accurately determine the nature of the hepatotoxicity.
Hy’s Law and Assessment of Hepatotoxicty
Hy’s law is based on the combined evidence of injury and decreased function in the absence of disease-induced damage. It is typically used to estimate severity and the likelihood that a product will cause increased incidence of severe hepatotoxicity.
Hy’s law requires the following 3 criteria be met:
1. A clinically significant increase in injury markers
2. A clinically significant decrease in function, and
3. Verification that the observed effects are in fact produced by the health product
In the Draft Guidance Document, the Ministry of Health is proposing that a single case of product-induced hepatotoxicity meeting the criteria of Hy’s Law be considered as a potential signal of hepatotoxicity and recommends that if more than one case is observed that serious risk vs. benefit assessment of the health product be conducted.
The document also recommends that non-clinical animal studies be carried out to assess the potential hepatotoxicity of the health product or substance in question to improve the clinical safety profile of the substance. The general assumption is that the higher the animal species to experience the hepatotoxicity or histopathological responses, the greater the potential of the substance has in eliciting a pathological response in humans. Animal models or in vitro tests are recommended to be used to gain insight into the mechanism of action behind a substance’s involvement in liver toxicity.
The proper assessment of hepatotoxicity can be confounded by many other factors such as alcohol or drug use, hepatitis, co-morbidity, genetic or metabolic disorders and pregnancy to name a few. If histological changes cannot be attributed to any of the confounding criteria, then product-inducted liver injury should be considered.
It has been proposed that any increase in liver injury parameters should be considered significant regardless of whether if the increase demonstrated statistical significance or not when compared to placebo controls. It has also been proposed that any changes in the pathological markers involved in liver toxicity be investigated to determine the clinical significance of the respective changes and that the frequency and duration of monitoring during a clinical trial should depend on the risk profile of the product and population of the study. Less frequent monitoring would be acceptable if systemic exposure is extremely low as with topical or ophthalmic products, for example.
Additionally, in healthy subjects, a conservative starting point for a product with no suspected hepatotoxicity may be to monitor hepatic function and injury every 2 to 4 weeks for the first three months and then every 2-3 months in longer clinical trials unless there is a suspicion of hepatotoxicity, in which case the hepatic function and injury should be monitored more frequently.
In subjects with known liver disease, or when testing a product or class of product of known or suspected hepatotoxicity, monitoring should be specifically tailored for each trial based on the nature of the disease and the health product.
The Ministry of Health is proposing that subject withdrawal be considered if:
• ALT and AST are greater than 5 times ULN and rising,
• ALT and AST remain greater than 5 times ULN with no change in total bilirubin for more than 2 weeks and/or a worsening of clinical symptoms with no other acceptable explanation, or
• the product meets Hy’s Law
Adverse Reaction Reporting for Cases of Hepatotoxicity
It has been outlined that hepatotoxicity reports are to contain certain key elements to properly assess the reaction. Key information to be provided with the report includes:
• History of previous exposure to the product;
• Information on potential contamination or adulteration of products;
• Patient characteristics (i.e. nutrition, smoking, alcohol use, medical history, etc.);
• Frequency of monitoring;
• Number of subjects who exceeded the threshold;
• Concomitant illness of autoimmunity;
• The time interval between product administration, the initial abnormal laboratory result and subsequent serial values;
• The number of subjects with levels which returned to normal;
• Results from any challenge with details on time and dose;
• All case reports of hepatotoxicity reported during clinical trials, including international reports of hepatotoxicity
• Diagnosis and management of all jaundice cases occurring during the clinical trials.
In summary, hepatotoxicity is a multifactorial condition which may be the result of various lifestyle choices. It is important to properly eliminate these confounding factors to properly assess the potential of health products in causing clinically significant hepatotoxic effects.
The Ministry of Health is requesting feedback from stakeholders regarding the information presented in their Draft Guidance Document. The deadline for the submission of comments is May 17, 2011. Comments should be provided in electronic format using the template found within the Draft Guidance Document and are to be directed to:
Bureau of Policy, Science and International Programs
Therapeutic Products Directorate
1600 Scott Street
Holland Cross, Tower B
2nd Floor, Address Locator 3102C5
Fax: (613) 941-1812
For further details please refer to the Draft Guidance Document located at: